This application claims the benefit of U.S. Provisional Patent Application Nos. 60/399,177, filed on Jul. 29, 2002, 60/399,176 filed on Jul. 29, 2002, 60/426,902 filed on Nov. 15, 2002 and 60/459,803 filed on Apr. 2, 2003, the contents of each of which are incorporated herein by reference.
1. Field of the Invention
This invention relates to myocardial imaging methods that are accomplished by administering doses of one or more adenosine A2A adenosine receptor agonists to a mammal undergoing myocardial imaging.
2. Description of the Art
Myocardial perfusion imaging (MPI) is a diagnostic technique useful for the detection and characterization of coronary artery disease. Perfusion imaging uses materials such as radionuclucides to identify areas of insufficient blood flow. In MPI, blood flow is measured at rest, and the result compared with the blood flow measured during exercise on a treadmill (cardiac stress testing), such exertion being necessary to stimulate blood flow. Unfortunately, many patients are unable to exercise at levels necessary to provide sufficient blood flow, due to medical conditions such as peripheral vascular disease, arthritis, and the like.
Therefore, a pharmacological agent that increases cardiac blood flow (CBF) for a short period of time would be of great benefit, particularly one that did not cause peripheral vasodilation. Vasodilators, for example dipyridamole, have been used for this purpose in patients prior to imaging with radionuclide. Dipyridamole is an effective vasodilator, but side effects such as pain and nausea limit the usefulness of treatment with this compound.
Adenosine, a naturally occurring nucleoside, also is useful as a vasodilator. Adenosine exerts its biological effects by interacting with a family of adenosine receptors characterized as subtypes A1, A2A, A2B, and A3. Adenoscan® (Fujisawa Healthcare Inc.) is a formulation of a naturally occurring adenosine. Adenoscan® has been marketed as an adjuvant in perfusion studies using radioactive thallium-201. However, its use is limited due to side effects such as flushing, chest discomfort, the urge to breathe deeply, headache, throat, neck, and jaw pain. These adverse effects of adenosine are due to the activation of other adenosine receptor subtypes other than A2A, which mediates the vasodilatory effects of adenosine. Additionally, the short half-life of adenosine necessitates multiple treatments during the procedure, further limiting its use. Adenoscan® is contraindicated in many patients including those with second-or third-degree block, sinus node disease, bronchoconstrictive or bronchospastic lung disease, and in patients with known hypersensitivity to the drug.
Other potent and selective agonists for the A2A adenosine receptor are known. For example, MRE-0470 (Medco) is an adenosine A2A receptor agonist that is a potent and selective derivative of adenosine. WRC-0470 (Medco) is an adenosine A2A agonist used as an adjuvant in imaging. In general, compounds such as these have a high affinity for the A2A receptor, and consequently, a long duration of action, which is undesirable in imaging.
Thus, there is still a need for a method of producing rapid and maximal coronary vasodilation in mammals without causing corresponding peripheral vasodilation, which would be useful for myocardial imaging with radionuclide agents. Preferred compounds would be selective for the A2A adenosine receptor and have a short duration of action (although longer acting than compounds such as adenosine), thus obviating the need for multiple dosing.